WO2024160253A1 - Multi-chamber container for eye drops and manufacturing method therefor - Google Patents

Multi-chamber container for eye drops and manufacturing method therefor Download PDF

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Publication number
WO2024160253A1
WO2024160253A1 PCT/CN2024/075261 CN2024075261W WO2024160253A1 WO 2024160253 A1 WO2024160253 A1 WO 2024160253A1 CN 2024075261 W CN2024075261 W CN 2024075261W WO 2024160253 A1 WO2024160253 A1 WO 2024160253A1
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WO
WIPO (PCT)
Prior art keywords
chamber
container
chambers
sealing
welding
Prior art date
Application number
PCT/CN2024/075261
Other languages
French (fr)
Chinese (zh)
Inventor
刘晔
张在娟
崔司琪
Original Assignee
苏州欧康维视生物科技有限公司
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Publication of WO2024160253A1 publication Critical patent/WO2024160253A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/0008—Introducing ophthalmic products into the ocular cavity or retaining products therein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
    • A61J1/2003—Accessories used in combination with means for transfer or mixing of fluids, e.g. for activating fluid flow, separating fluids, filtering fluid or venting
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
    • A61J1/2093—Containers having several compartments for products to be mixed

Definitions

  • the present invention relates to a container for storing and administering eye drops, and also to a method for preparing such a multi-chamber container.
  • the pH range of drugs that can be tolerated by the human eye is 5.0 to 9.0, and the pH range of eye drops is usually roughly within this range.
  • the pH of eye drops is less than 5.0 or greater than 11.4, it will cause obvious irritation to the eyes.
  • some common active ingredients of ophthalmic drugs show instability caused by easy hydrolysis.
  • drugs with ester bonds or amide bonds that are easily hydrolyzed.
  • the eye discomfort caused by medication often leads to poor compliance.
  • the current commercially available products still use a solution pH that is not conducive to the stable preservation of eye drops, and are therefore not suitable for long-term storage.
  • Containers with multiple chambers have been used to store medical mixed solutions with time instability.
  • One type of container is an isolation structure formed by a removable seal. The removable seal can be broken by tension or by pressing on the adjacent container chamber filled with liquid.
  • a multi-chamber container with a removable seal can form a larger opening to facilitate full mixing between solutions.
  • this type of container has only been reported to use a flexible bag made of a film material with high elasticity and high heat resistance (see CN1976668A).
  • the prior art also has a multi-chamber structure that uses a rigid, easily breakable material to isolate the chambers.
  • the advantage of this multi-chamber container is that it is highly versatile, but its isolation components can often only form a limited notch cross section, which is not conducive to the full mixing of the solutions, and the damage of the isolation structure leads to a significantly increased number of undesirable particles in the mixed solution (see EP0378183).
  • the increased insoluble particles are particularly related to the discomfort when using the ophthalmic solution, and may even lead to non-compliance with the mandatory standards related to eye drops.
  • the object of the present invention is to provide an eye drop container having at least two chambers separated from each other by a detachable seal and capable of being easily and reliably opened by an ordinary person without professional training and without the aid of any special tools, thereby ensuring the stability of the contained ophthalmic solution at low or high pH and effectively avoiding the discomfort caused by non-physiological pH and insoluble particles irritating the human eye.
  • the present invention provides a multi-chamber container for eye drops, wherein the body of the container is composed of at least two chambers including a first chamber and a second chamber, wherein the first chamber is connected to an outlet, and the remaining chambers are connected to the first chamber or other chambers, and adjacent chambers are separated by a sealing part (2) and are not connected to each other; wherein, when an external force is applied to the outer wall of one of the two adjacent chambers, the sealing part between the two adjacent chambers will be irreversibly detached, and when all the sealing parts are detached, each chamber will be directly or indirectly connected to the first chamber.
  • a sealing cover is further provided on the outflow port, and the sealing cover can be opened once or can be opened and closed repeatedly.
  • the material of the container body is rigid plastic.
  • the multi-chamber container is composed of two chambers.
  • the sealing portion is formed by using ultrasonic welding of the container body with an electric cylinder torque of 232 to 266 Newtons and a welding time of 0.290 to 0.370 seconds.
  • the sealing part is formed by welding the container body together using ultrasonic waves with an amplitude of 10% to 42% and a welding time of 0.19 to 0.64 s, preferably ultrasonic waves with an amplitude of 36% to 39% and a welding time of 0.47 to 0.49 s.
  • the external force capable of irreversibly disengaging the sealing portion is no more than the average pinching force of a 5-7 year old child's fingers, preferably no more than about 17-27 Newtons (N).
  • the container further comprises a container tail portion (7), and the tail portion is formed under sealing conditions of a cylinder pressure of 2.0 to 2.5 bar and a welding time of 0.16 to 0.22 s.
  • the container further comprises a container tail (7), wherein the tail is The sealing is formed under the conditions that the ultrasonic amplitude is 43% or more and the welding time is 0.65s or more.
  • the body of the container is tubular.
  • the tube has a length of 15 to 180 mm and an inner diameter of 4 to 30 mm.
  • the thickness of the rigid plastic forming the container is 200 to 2000 ⁇ m, preferably 350 to 500 ⁇ m, and more preferably 380 to 400 ⁇ m.
  • the container has a capacity of 0.2 ml or more and 20 ml or less.
  • the present invention further provides an eye drop product in which different medicaments are respectively filled in multiple chambers of the aforementioned multi-chamber container, wherein at least one of the medicaments has a pH value lower than about 5.3 or higher than about 8.3, and a mixed solution formed by mixing the medicaments filled in the multiple chambers has a pH value of about 5.3 to about 8.3, and the stability (e.g., hydrolysis stability) of at least one medicament is higher than the stability of the mixed solution formed after mixing the medicaments filled in different chambers.
  • the stability e.g., hydrolysis stability
  • the present invention also provides a method for preparing the above-mentioned eye drop product, the method comprising:
  • An outlet is formed at one end of the hollow structure, and a cover is preferably provided on the outflow product, the cover being disposable or re-openable and re-closable, and the outlet is communicated with the first chamber;
  • the last chamber is sealed by welding to form the tail of the container;
  • the various medicines filled in the chambers can eventually be directly or indirectly mixed with the medicine in the first chamber by releasing the sealing parts, and then discharged from the outflow port.
  • each sealing part is formed by performing virtual welding using an ultrasonic wave with a torque force of 232 to 266 Newtons and a welding time of 0.290 to 0.370 seconds, and using The last chamber is sealed by ultrasonic welding with a cylinder pressure of 2.0 to 2.5 bar and a welding time of 0.16 to 0.22 s to form the tail of the container.
  • each sealing portion (2) is formed by performing cold welding using ultrasonic waves with an amplitude of 10% to 42% and a welding time of 0.19 to 0.64 s, preferably ultrasonic waves with an amplitude of 36% to 39% and a welding time of 0.47 to 0.49 s, and the last chamber is welded and sealed under the sealing conditions of an amplitude of more than 43% and a welding time of more than 0.65 s to form the tail (7) of the container.
  • the material of the container body is rigid plastic.
  • the multi-chamber container consists of two chambers.
  • the external force capable of irreversibly disengaging the sealing portion is no more than the average pinching force of a 5-7 year old child's fingers, preferably no more than about 17-27 Newtons (N).
  • the body of the container is in a tubular shape.
  • the tube has a length of 15 to 180 mm and an inner diameter of 4 to 30 mm.
  • the thickness of the rigid plastic is 200 to 2000 ⁇ m, preferably 350 to 500 ⁇ m, and more preferably 380 to 400 ⁇ m.
  • the multi-chamber container has a capacity of 0.2 ml or more and 20 ml or less.
  • the virtual welding structure of the present invention can stably separate different chambers, and maintain structural stability under the action of common external forces during production, transportation, storage, and sales. It can be easily pinched open from the outside by everyone from children to the elderly without the assistance of special tools. The pinching process does not destroy the sealed environment inside the container, and the sterile environment is guaranteed. The very small amount of insoluble particles generated after pinching will not damage the quality of the drug.
  • the container of the present invention has a small overall volume, and the total loading amount is about 20 ml or less, and is mainly used as a container for eye drops and other medical solutions with a small volume.
  • the loading amount of the container of the present invention can be a single dose, and can also meet the requirements of multiple doses (usually not more than a single monthly dose).
  • the small dose and good sealing performance of the container of the present invention make it still meet the relevant requirements of medicines without adding antibacterial agents such as benzalkonium chloride. Thereby avoiding the irritation of antibacterial substances to human organs, especially sensitive organs such as eyeballs.
  • FIG. 1 is an example of a multi-chamber eye drop container in the present application.
  • container body 2 virtual weld; 3, first chamber; 4, second chamber; 5, outflow port; 6, cover; 7, container tail.
  • the container of the present invention will be further described below with reference to the accompanying drawings and specific embodiments.
  • the examples given are only for illustrating the present invention, not for limiting the scope of the present invention.
  • the examples provided below can be used as a guide for further improvements by those of ordinary skill in the art, and do not constitute a limitation of the present invention in any way.
  • the term “including” or “comprising” means that the structure and process include the components or steps described, but do not exclude other components or steps.
  • the term “approximately” refers to the common error range of the corresponding value that is easily known to those skilled in the art.
  • the value or parameter described in this article in the form of "approximately” includes the value or parameter itself.
  • multi-chamber not only includes the case of two chambers illustrated in the specific embodiment, but also includes the case of more chambers that a person skilled in the art can easily think of based on the content disclosed in the present invention and specific needs, such as three or more.
  • rigid plastic in this article refers to a plastic that can be deformed due to an external force applied by, for example, finger pinching, and automatically restores its original shape after the external force is removed.
  • conventional plastic materials used in single-dose or multi-dose eye drops bottles see the "9621 General Requirements and Guidelines for Drug Packaging Materials” in the four general rules of the "Chinese Pharmacopoeia 2015 Edition”;”National Drug Packaging Material Standards", organized and compiled by the China Food and Drug Inspection Institute, China Medical Science and Technology Press).
  • the plastic used to prepare the container of the present invention can be any plastic known in the art that is suitable for preparing single-dose or multi-dose medical solution bottles, as long as the elastic modulus it has can achieve the reversible deformation and recovery of the present invention.
  • the rigid plastic used in the present invention can be listed as polyolefin resins, including but not limited to polyethylene resins such as low-density polyethylene, polypropylene resins such as polypropylene, cyclic polyolefin resins, and composite layer materials containing different polyolefins.
  • the rigid plastic used in the present invention can also be found in, for example, the "Quick Reference Manual for Common Plastic Varieties" compiled by Qi Guiliang et al.
  • the rigid plastic in the present invention, reference may also be made to the examples described in the invention patent application entitled “A low-concentration atropine drug product and a method for manufacturing the same” filed by the applicant on the same date as the filing date of the present application. The entire text of the application on the same date is incorporated into the present application by reference.
  • the thickness of the rigid plastic used in the container of the present invention can achieve the reversible deformation and recovery required by the container of the present invention, and has the mechanical strength required by the medical container (especially the eye drop container).
  • the rigid plastic used in the container of the present invention has a thickness of 200 to 2000 ⁇ m, preferably 350 to 500 ⁇ m, and more preferably 380 to 400 ⁇ m.
  • the resin used in the container of the present invention can also be laminated with a metal material such as aluminum foil.
  • the thickness of the rigid plastic of the container of the present invention is the thickness after including all the laminated materials.
  • the container of the present invention can be any suitable shape, as long as it is suitable for accommodating single-dose or multi-dose pharmaceutical solutions.
  • the container of the present invention is made of tubular rigid plastics with a certain length and diameter.
  • tubular refers to a hollow cylindrical structure with a certain length.
  • the length of the tubular is significantly greater than its diameter.
  • the tubular has a length of 15 to 180 mm and an inner diameter of 4 to 30 mm.
  • the container of the present invention has a capacity suitable for holding a single dose or multiple doses of a pharmaceutical solution.
  • capacity refers to the sum of the volume of solutions that all chambers included in the container can hold.
  • the container of the present invention has a capacity of more than 0.2 ml and less than 20 ml.
  • the term "detachable sealing member” and “virtual weld” are used interchangeably, and refer to a structure mainly formed by the container body of the present invention through a virtual welding process, which can isolate different chambers of the container of the present invention and can be peeled or detached under a certain force.
  • the virtual weld of the container of the present invention can be applied to any design, as long as it can be easily detached due to the pressure applied by the user on any chamber wall for the purpose of use, and will not be undesirably detached due to normal external forces during the preparation, packaging, transportation, sales, etc.
  • the virtual weld can be a narrow and long straight-line structure.
  • the virtual weld can also be in the shape of a curved arc or an intersecting straight line with an angle.
  • the virtual weld has a uniform and equal width.
  • the virtual weld has a variable width.
  • the width of the virtual weld is 1 to 20 mm, preferably 2 to 8 mm, and more preferably 4 mm.
  • different medical solutions are filled in the multiple chambers of the container of the present invention.
  • a drug that is easily hydrolyzed can be filled in the first chamber, and an aqueous solution of a pharmaceutically acceptable excipient component can be filled in the second chamber.
  • the drugs that can be filled in the first chamber can include ester drugs such as tetracaine hydrochloride, cocaine hydrochloride, propantheline, atropine sulfate, and homatropine hydrobromide, amide drugs, etc.
  • Non-limiting examples of drugs that can be filled in the second chamber include but are not limited to buffer salts, osmotic pressure regulators, preservatives and/or metal ion chelators, etc. It can be understood by those skilled in the art that the contents in the chambers of the container of the present invention can be changed, for example, the solutions in the two chambers can be replaced with other suitable solutions, as long as they can eventually be mixed to form eye drops that can be directly applied to the eyes.
  • the ester drugs in the first chamber can be replaced with lactone drugs such as pilocarpine nitrate and warfarin sodium.
  • the assignment of the filling solution to the container chamber can also be changed, that is, an aqueous solution of a pharmaceutically acceptable excipient such as a buffer solution can be contained in the first chamber, and a readily hydrolyzable drug solution can be contained in the second chamber.
  • a pharmaceutically acceptable excipient such as a buffer solution
  • a readily hydrolyzable drug solution can be contained in the second chamber.
  • the user should evenly mix the two solutions together just before administration to form an eye drop for direct administration to the eye.
  • the outflow port and the cover used in the container of the present invention can adopt any outflow port and cover structure conventionally used in the art, as long as the solution in the container is allowed to be squeezed out of the container in a dropwise manner when the cover is opened.
  • the outflow port of the container of the present invention can also be a closed port that does not need to be covered, as long as it can be easily opened when in use.
  • the outflow port of the container of the present invention can also be a cover that can be repeatedly opened and closed and connected to or disconnected from the multi-chamber container body.
  • the position of the virtual welding can be easily determined according to the amount of the target solution injected. For example, when the two target solutions injected are equal, the virtual welding is performed near the midpoint of the container body.
  • the process for virtual welding the container of the present invention preferably uses ultrasonic welding, but other suitable welding methods can also be selected.
  • an ultrasonic welding machine model STD20-1500W
  • an electric actuator of model LEYH32NZC-50M can be cited
  • an ultrasonic welding machine with an ultrasonic generator of model EDG-2020 can be used.
  • the process used to seal the tail is a process commonly used in the art for welding plastic materials, including but not limited to heat fusion welding, ultrasonic welding, etc.
  • ultrasonic welding is used to seal the tail of the container of the present invention.
  • an ultrasonic welding machine (model STD-2000W) with a cylinder model MD81840-50Z or a The ultrasonic welding machine is carried out by the ultrasonic generator of EDG-2020.
  • Example 1 Structure, composition and use of container
  • FIG1 shows a specific embodiment of the present application.
  • the body 1 of the multi-chamber container comprises a first chamber 3 and a second chamber 4.
  • a sealing portion 2 ie, a virtual weld is provided between the first chamber 3 and the second chamber 4.
  • the container body 1 is made of polyolefin resin, which allows cold welding using ultrasonic technology and has transparency, hygiene, and appropriate elasticity and rigidity.
  • the first chamber 3 or the second chamber 4 is pressurized and the internal pressure of the chamber is increased, so that the virtual weld can be opened, and the first chamber 3 and the second chamber 4 are connected to each other, and the pharmaceutical solutions contained in the two chambers are mixed together.
  • the tail 7 of the multi-chamber container will not be damaged by manually applying pressure, and the contents of the container will not flow out of the tail undesirably.
  • the cover 6 at the front end of the outflow port 5 is twisted off and removed, so that the outflow port 5 is in an open state, and the formed mixed solution can be squeezed out from the outflow port 5 in a drop-by-drop manner.
  • the multi-chamber eye drop product of the present invention can be made by the following process.
  • the body of the double-chamber container was prepared using a low-density polyethylene (LDPE) hose with a diameter of 13.0 mm ( ⁇ 0.2 mm) and open ends.
  • LDPE low-density polyethylene
  • the polyolefin hose is shortened in sequence to form a short tube with the same length.
  • the specific length can be adjusted appropriately according to the planned amount of medicine to be loaded, and is generally not less than about 40 mm.
  • the hose is shortened to a length of 40 mm.
  • a conventional blow molding process is adopted to form a flow outlet 5 at one end of the shortened hose, and the flow outlet is communicated with the chamber in the container body.
  • the container is also provided with a cover 6 suitable for the flow outlet 5 for closing the flow outlet.
  • the first drug solution was injected into the container body 1 from the other end of the hose where no outflow port was formed. Then, ultrasonic welding was performed at the midpoint of the length of the container body 1 using an ultrasonic welding machine of model STD20-1500W with an electric actuator of model LEYH32NZC-50M, and the welding time was 0.290 to 0.370 s.
  • the container body 1 After cold welding, the container body 1 forms two chambers that are not connected to each other, namely, a first chamber 3 with an outflow port 5 and a second chamber 4 away from the outflow port 5 and connected to the first chamber 3 by cold welding, wherein the first chamber 3 has been filled with the first pharmaceutical solution, and the other is a hollow structure that has not yet received the solution.
  • This embodiment tests the complete sealing rate when the container tail is sealed using different preparation parameters with cylinder pressure of 1.7-2.5 bar and welding time of 0.16-0.22 s. The results are shown in the following table A).
  • This embodiment tests the complete sealing rate and pinching rate when different preparation parameters are used to seal the container virtual weld seam with the electric cylinder torque of 232-266N and welding time of 0.200-0.370s.
  • the results are shown in the following table B) according to conventional instrument measurement.
  • group A represents a virtual weld with a welding time of 0.345s and a cylinder torque of 238.6N
  • group B represents a virtual weld with a welding time of 0.305s and a cylinder torque of 241N.
  • the multi-chamber eye drop product of the present invention can also be made by the following process.
  • the polyolefin hose is sequentially subjected to outlet molding, filling with the first solution, virtual welding, filling with the second solution, and tail sealing.
  • the polyolefin hose used in this example is a polypropylene hose, and the virtual welding and tail sealing are completed using the same ultrasonic welding equipment by changing the amplitude and welding time of the ultrasonic generator (model EDG-2020).
  • This embodiment tests the complete sealing rate when the container tail is sealed using different preparation parameters with an amplitude of 10-45% and a welding time of 0.19-0.95s. The results are shown in the following table D).
  • This example tests the complete sealing rate and pinching rate when different preparation parameters are used to seal and form a container virtual weld seam with an amplitude of 10-45% and a welding time of 0.19-1.10s.
  • the results are shown in the following table E) according to conventional instrument measurements.
  • Group A represents a virtual weld with a welding time of 0.47s and an amplitude of 39%
  • Group B represents a virtual weld with a welding time of 0.49s and an amplitude of 36%.
  • the present invention uses the following liquid composition to measure the insoluble particles in the mixed solution after pinching the virtual weld seam and mixing:
  • Composition 1 is a composition of Composition 1:
  • Tetracaine hydrochloride cocaine hydrochloride, propantheline, etc. 0.01-0.05%;
  • the balance is water
  • the pH was adjusted to 3.5-4.5.
  • the pH was adjusted to 7.0-8.5.
  • Composition 2 is a composition of Composition 2:
  • the balance is water
  • the pH was adjusted to 3-4.
  • the pH was adjusted to 7-8.
  • the amount of insoluble particles contained in the ophthalmic solution in pure water, in a single-chamber container prepared by the tail-sealing process, and in a double-chamber container prepared by the preferred process of the present invention was measured.
  • the measurement results are shown in the following Table G).

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Abstract

A multi-chamber container for storing and administering eye drops, and a manufacturing method therefor. The container is provided with at least two chambers (3, 4) that are completely separated by a detachable sealing portion (2), and these chambers (3, 4) respectively dependently package different types of medicaments, thereby avoiding changes over time when these medicaments are mixed together. The sealing portion (2) in the container can be detached under the condition that external force is applied to one of the chambers (3, 4) of the container, so that different medicaments that are independently packaged are mixed together in a sterile state, thereby forming a mixed solution that can be directly administered to eyes.

Description

一种滴眼液用多腔室容器及其制备方法A multi-chamber container for eye drops and preparation method thereof 技术领域Technical Field
本发明涉及一种用于储存和施用滴眼液的容器，还涉及用于制备这种多腔室容器的方法。The present invention relates to a container for storing and administering eye drops, and also to a method for preparing such a multi-chamber container.
背景技术Background Art
人眼部可耐受的药物pH范围为5.0～9.0，滴眼液的pH范围通常大致在此区间内，当滴眼液的pH小于5.0或大于11.4时，会对眼部产生明显的刺激性。然而，在上述人眼可耐受的pH范围内，部分常见的眼药活性成分表现出易发生水解而导致的不稳定性。例如，具有易于水解的酯键或酰胺键类药物。尤其是对于近视高发群体的儿童和青少年而言，用药后造成的眼部不适感往往导致较差的顺应性。为了降低眼部刺激性，目前的市售制品仍然采用不利于滴眼液稳定保存的溶液pH，因此不适宜长期存放。The pH range of drugs that can be tolerated by the human eye is 5.0 to 9.0, and the pH range of eye drops is usually roughly within this range. When the pH of eye drops is less than 5.0 or greater than 11.4, it will cause obvious irritation to the eyes. However, within the above pH range that can be tolerated by the human eye, some common active ingredients of ophthalmic drugs show instability caused by easy hydrolysis. For example, drugs with ester bonds or amide bonds that are easily hydrolyzed. Especially for children and adolescents who are in the high-risk group for myopia, the eye discomfort caused by medication often leads to poor compliance. In order to reduce eye irritation, the current commercially available products still use a solution pH that is not conducive to the stable preservation of eye drops, and are therefore not suitable for long-term storage.
具有多个腔室的容器已被用于收纳具有经时不稳定性的医用混合溶液。一类容器是利用可脱开密封件形成隔离结构。可脱开密封件可以通过张力或者在与之相邻的装满液体的容器腔室上按压而发生破裂。具有可脱开密封件的多腔室容器能够形成更大的开口，便于溶液间充分混合。但是这类容器仅报道过使用具有高弹性和高耐热性的薄膜材料制成的柔性袋(参见CN1976668A)。对于这类具有多腔室的柔性输液袋而言，存在几个普遍需要解决的问题：一是可脱开密封件在到达目标使用者时已经由于运输等过程中不可避免的外力而被不适当地打开；二是在完整地到达目标使用者之后，可脱开密封件不易打开，导致无法形成目标混合溶液。据报道，对于具有多腔室的医用注射液柔性袋，优选使用拉开法或卷动法使密封部脱开并混合内容物，但即使是经过专业训练的临床工作者或护理人员也不能保证容易且安全的打开大多数带有可脱开密封部的柔性容器，因而普通人(尤其是例如老年人、儿童、具有手部残疾或肌力减弱的个体)通常无法独立地在缺少特殊工具辅助的情况下使用；三是这种柔性袋的薄膜材料和打开方式导致其不适合装载总量较小的医用液体，且其使用方式往往为一次性的。因此，在需要逐滴给药的滴眼液领域，目前常用的容器仍然是由具有一定刚性的塑料等材质制成的单腔室滴眼液瓶。Containers with multiple chambers have been used to store medical mixed solutions with time instability. One type of container is an isolation structure formed by a removable seal. The removable seal can be broken by tension or by pressing on the adjacent container chamber filled with liquid. A multi-chamber container with a removable seal can form a larger opening to facilitate full mixing between solutions. However, this type of container has only been reported to use a flexible bag made of a film material with high elasticity and high heat resistance (see CN1976668A). For this type of flexible infusion bag with multiple chambers, there are several common problems that need to be solved: one is that the removable seal has been improperly opened due to inevitable external forces during transportation when it reaches the target user; the second is that after reaching the target user intact, the removable seal is not easy to open, resulting in the inability to form a target mixed solution. It is reported that for a flexible bag for medical injection with multiple chambers, it is preferred to use a pulling method or a rolling method to disengage the seal and mix the contents, but even professionally trained clinical workers or nursing staff cannot guarantee easy and safe opening of most flexible containers with removable seals, so ordinary people (especially, for example, the elderly, children, individuals with hand disabilities or weakened muscle strength) are usually unable to use them independently without the assistance of special tools; third, the film material and opening method of this flexible bag make it unsuitable for loading a small total amount of medical liquid, and its use method is often disposable. Therefore, in the field of eye drops that require drop-by-drop administration, the currently commonly used container is still a single-chamber eye drop bottle made of a material such as plastic with a certain rigidity.
现有技术也有采用以刚性的易破碎材料制成的隔离部件进行腔室间隔离的多腔 室容器。这种多腔室容器的优点是具有高通用性，但其隔离部件往往仅能形成有限的缺口横截面而不利于溶液充分混合，以及由于隔离结构破损而导致混合溶液中含有数量显著提高的不期望颗粒(参见EP0378183)。增加的不溶性颗粒尤其与眼用溶液使用时的不适感相关，甚至可能导致不符合滴眼液相关的强制标准。The prior art also has a multi-chamber structure that uses a rigid, easily breakable material to isolate the chambers. The advantage of this multi-chamber container is that it is highly versatile, but its isolation components can often only form a limited notch cross section, which is not conducive to the full mixing of the solutions, and the damage of the isolation structure leads to a significantly increased number of undesirable particles in the mixed solution (see EP0378183). The increased insoluble particles are particularly related to the discomfort when using the ophthalmic solution, and may even lead to non-compliance with the mandatory standards related to eye drops.
发明内容Summary of the invention
本发明的目的在于提供一种具有至少两个由可脱开的密封件相互隔离的腔室，且能够被未经专业训练的普通人在无需任何特殊工具辅助的条件下、容易且可靠地打开的滴眼液用容器，从而既保证所收纳的眼用溶液在低pH或高pH下的稳定性，又能够有效避免非生理pH及不溶性颗粒刺激人眼引起的不适感。The object of the present invention is to provide an eye drop container having at least two chambers separated from each other by a detachable seal and capable of being easily and reliably opened by an ordinary person without professional training and without the aid of any special tools, thereby ensuring the stability of the contained ophthalmic solution at low or high pH and effectively avoiding the discomfort caused by non-physiological pH and insoluble particles irritating the human eye.
为了解决前述问题，本发明提供一种滴眼液用多腔室容器，所述容器的本体由至少包括第一腔室和第二腔室在内的两个以上的腔室组成，所述第一腔室与流出口连通，其余腔室与第一腔室或其它腔室连接，相邻的腔室被密封部分(2)所分隔而互不连通；其中，在对相邻的两个腔室之一的外壁施加外力的条件下，将导致该相邻的两个腔室之间的所述密封部分不可逆地脱开，全部密封部分均脱开时，每个腔室都将直接或间接与第一腔室连通。In order to solve the above-mentioned problems, the present invention provides a multi-chamber container for eye drops, wherein the body of the container is composed of at least two chambers including a first chamber and a second chamber, wherein the first chamber is connected to an outlet, and the remaining chambers are connected to the first chamber or other chambers, and adjacent chambers are separated by a sealing part (2) and are not connected to each other; wherein, when an external force is applied to the outer wall of one of the two adjacent chambers, the sealing part between the two adjacent chambers will be irreversibly detached, and when all the sealing parts are detached, each chamber will be directly or indirectly connected to the first chamber.
根据本发明前述的多腔室容器，所述流出口上还设置有封盖，该封盖为一次性开启的或者为可重复启闭的。According to the aforementioned multi-chamber container of the present invention, a sealing cover is further provided on the outflow port, and the sealing cover can be opened once or can be opened and closed repeatedly.
根据本发明前述的多腔室容器，所述容器本体的材质为刚性塑料。According to the aforementioned multi-chamber container of the present invention, the material of the container body is rigid plastic.
根据本发明前述的多腔室容器，所述多腔室容器由两个腔室构成。According to the aforementioned multi-chamber container of the present invention, the multi-chamber container is composed of two chambers.
根据本发明前述的多腔室容器，所述密封部分是使用电缸扭力力度为232～266牛、焊接时间为0.290～0.370s的超声波将容器本体虚焊在一起而形成的。According to the aforementioned multi-chamber container of the present invention, the sealing portion is formed by using ultrasonic welding of the container body with an electric cylinder torque of 232 to 266 Newtons and a welding time of 0.290 to 0.370 seconds.
根据本发明前述的多腔室容器，所述密封部分是使用振幅为10％～42％、焊接时间为0.19～0.64s的超声波，优选振幅为36％～39％、焊接时间为0.47～0.49s的超声波将所述容器本体虚焊在一起而形成的。According to the aforementioned multi-chamber container of the present invention, the sealing part is formed by welding the container body together using ultrasonic waves with an amplitude of 10% to 42% and a welding time of 0.19 to 0.64 s, preferably ultrasonic waves with an amplitude of 36% to 39% and a welding time of 0.47 to 0.49 s.
根据本发明前述的多腔室容器，所述能够使密封部分不可逆脱开的外力为不超过5～7岁儿童手指的平均捏合力，优选不超过约17～27牛顿(N)。According to the aforementioned multi-chamber container of the present invention, the external force capable of irreversibly disengaging the sealing portion is no more than the average pinching force of a 5-7 year old child's fingers, preferably no more than about 17-27 Newtons (N).
根据本发明前述的多腔室容器，所述容器还包含容器尾部(7)，所述尾部是在气缸气压为2.0～2.5bar、焊接时间为0.16～0.22s的封接条件下形成的。According to the aforementioned multi-chamber container of the present invention, the container further comprises a container tail portion (7), and the tail portion is formed under sealing conditions of a cylinder pressure of 2.0 to 2.5 bar and a welding time of 0.16 to 0.22 s.
根据本发明前述的多腔室容器，所述容器还包含容器尾部(7)，所述尾部是在 超声波振幅为43％以上、焊接时间为0.65s以上的封接条件下形成的。According to the aforementioned multi-chamber container of the present invention, the container further comprises a container tail (7), wherein the tail is The sealing is formed under the conditions that the ultrasonic amplitude is 43% or more and the welding time is 0.65s or more.
根据本发明前述的多腔室容器，所述容器的本体为管状。According to the aforementioned multi-chamber container of the present invention, the body of the container is tubular.
根据本发明前述的多腔室容器，所述管状具有15～180mm的长度、4～30mm的内直径。According to the aforementioned multi-chamber container of the present invention, the tube has a length of 15 to 180 mm and an inner diameter of 4 to 30 mm.
根据本发明前述的多腔室容器，形成所述容器的刚性塑料的厚度为200～2000μm，优选350～500μm，更优选380～400μm。According to the aforementioned multi-chamber container of the present invention, the thickness of the rigid plastic forming the container is 200 to 2000 μm, preferably 350 to 500 μm, and more preferably 380 to 400 μm.
根据本发明前述的多腔室容器，所述容器具有0.2ml以上且20ml以下的容量。According to the aforementioned multi-chamber container of the present invention, the container has a capacity of 0.2 ml or more and 20 ml or less.
本发明进一步提供一种在前述多腔室容器的多个腔室中分别装填有不同药剂的滴眼液制品，其中所述药剂中的至少一种具有低于约5.3或高于约8.3的pH值，装填在多个腔室中的药剂混合所形成的混合溶液则具有约5.3至约8.3的pH值，且至少一种药剂的稳定性(例如水解稳定性)高于装填在不同腔室中的药剂混合后所形成的混合溶液的稳定性。The present invention further provides an eye drop product in which different medicaments are respectively filled in multiple chambers of the aforementioned multi-chamber container, wherein at least one of the medicaments has a pH value lower than about 5.3 or higher than about 8.3, and a mixed solution formed by mixing the medicaments filled in the multiple chambers has a pH value of about 5.3 to about 8.3, and the stability (e.g., hydrolysis stability) of at least one medicament is higher than the stability of the mixed solution formed after mixing the medicaments filled in different chambers.
本发明还提供了一种用于制备前述滴眼液制品的方法，所述方法包括：The present invention also provides a method for preparing the above-mentioned eye drop product, the method comprising:
选择适宜制成容器本体的材质，所述材质具有两端或多端开口的空心结构；Select a material suitable for making the container body, wherein the material has a hollow structure with two or more openings;
在所述空心结构的一端开口形成一个流出口，并优选在流出品上设置封盖，该封盖为一次性开启的或者为可重复启闭的，所述流出口与第一腔室连通；An outlet is formed at one end of the hollow structure, and a cover is preferably provided on the outflow product, the cover being disposable or re-openable and re-closable, and the outlet is communicated with the first chamber;
在所述流出口处于封闭状态的情况下，在其它端开口向所述空心结构中填充第一指定体积的第一药剂；When the outflow port is in a closed state, filling the hollow structure with a first designated volume of a first medicament at the other end opening;
在所述空心结构的与所述第一指定体积相对应的位置处进行虚焊，形成可脱开的密封部分，从而在所述可脱开的密封部分与所述流出口之间形成内部含有所述第一药剂的、密封的第一腔室；Performing cold welding at a position of the hollow structure corresponding to the first designated volume to form a detachable sealing portion, thereby forming a sealed first chamber containing the first medicament between the detachable sealing portion and the outflow port;
自其它端开口将第二指定体积的第二药剂继续填充至该开口与可脱开的密封部分之间形成的第二腔室，所述第二药剂不同于所述第一药剂；Continue filling a second prescribed volume of a second medicament into a second chamber formed between the other end opening and the releasable sealing portion, wherein the second medicament is different from the first medicament;
以此类推，任选形成通过密封部分相互分隔的装填有更多不同药剂的更多腔室；By analogy, more chambers filled with more different medicines separated from each other by sealing portions are optionally formed;
在将最后一种药剂装填至最后一个腔室之后，通过焊接密封该最后一个腔室形成所述容器的尾部；After the last medicine is filled into the last chamber, the last chamber is sealed by welding to form the tail of the container;
如此，各腔室中装填的各种药剂最终均可通过脱开各密封部分而直接或间接与第一腔室中的药剂混合，从而自流出口排出。In this way, the various medicines filled in the chambers can eventually be directly or indirectly mixed with the medicine in the first chamber by releasing the sealing parts, and then discharged from the outflow port.
根据本发明的制备滴眼液制品的方法，其中通过使用电缸扭力力度为232～266牛、焊接时间为0.290～0.370s的超声波进行虚焊以形成所述每个密封部分，并使用 气缸压力为2.0～2.5bar、焊接时间为0.16～0.22s的超声波焊接密封最后一个腔室以形成所述容器的尾部。According to the method for preparing an eye drop product of the present invention, each sealing part is formed by performing virtual welding using an ultrasonic wave with a torque force of 232 to 266 Newtons and a welding time of 0.290 to 0.370 seconds, and using The last chamber is sealed by ultrasonic welding with a cylinder pressure of 2.0 to 2.5 bar and a welding time of 0.16 to 0.22 s to form the tail of the container.
根据本发明的制备滴眼液制品的方法，其中通过使用振幅为10％～42％、焊接时间为0.19～0.64s的超声波，优选振幅为36％～39％、焊接时间为0.47～0.49s的超声波进行虚焊以形成所述每个密封部分(2)，并在振幅为43％以上、焊接时间为0.65s以上的封接条件下焊接密封最后一个腔室以形成所述容器的尾部(7)。According to the method for preparing an eye drop product of the present invention, each sealing portion (2) is formed by performing cold welding using ultrasonic waves with an amplitude of 10% to 42% and a welding time of 0.19 to 0.64 s, preferably ultrasonic waves with an amplitude of 36% to 39% and a welding time of 0.47 to 0.49 s, and the last chamber is welded and sealed under the sealing conditions of an amplitude of more than 43% and a welding time of more than 0.65 s to form the tail (7) of the container.
根据本发明的制备滴眼液制品的方法，所述容器本体的材质为刚性塑料。According to the method for preparing an eye drop product of the present invention, the material of the container body is rigid plastic.
根据本发明的制备滴眼液制品的方法，所述多腔室容器由两个腔室构成。According to the method for preparing an eye drop product of the present invention, the multi-chamber container consists of two chambers.
根据本发明的制备滴眼液制品的方法，所述能够使密封部分不可逆脱开的外力为不超过5～7岁儿童手指的平均捏合力，优选不超过约17～27牛顿(N)。According to the method for preparing an eye drop preparation of the present invention, the external force capable of irreversibly disengaging the sealing portion is no more than the average pinching force of a 5-7 year old child's fingers, preferably no more than about 17-27 Newtons (N).
根据本发明的制备滴眼液制品的方法，所述容器的本体为管状。According to the method for preparing an eye drop product of the present invention, the body of the container is in a tubular shape.
根据本发明的制备滴眼液制品的方法，所述管状具有15～180mm的长度、4～30mm的内直径。According to the method for preparing an eye drop product of the present invention, the tube has a length of 15 to 180 mm and an inner diameter of 4 to 30 mm.
根据本发明的制备滴眼液制品的方法，所述刚性塑料的厚度为200～2000μm，优选350～500μm，更优选380～400μm。According to the method for preparing eye drop products of the present invention, the thickness of the rigid plastic is 200 to 2000 μm, preferably 350 to 500 μm, and more preferably 380 to 400 μm.
根据本发明的制备滴眼液制品的方法，所述多腔室容器具有0.2ml以上且20ml以下的容量。According to the method for preparing an eye drop product of the present invention, the multi-chamber container has a capacity of 0.2 ml or more and 20 ml or less.
本发明的多腔室容器或滴眼液制品可以实现以下优异的效果：The multi-chamber container or eye drop product of the present invention can achieve the following excellent effects:
1、由于不同腔室在使用前相互独立，能够使一些难以保存的药物在使用前得到较为适宜的保存环境，而在使用时通过临时混合使得最终配方达成适宜使用的条件，从而在增加用药依从性的同时，延长药物货架期。1. Since different chambers are independent of each other before use, some difficult-to-preserve drugs can be stored in a more suitable environment before use. During use, temporary mixing can be performed to make the final formula suitable for use, thereby increasing medication compliance and extending the shelf life of the drug.
2、本发明的虚焊结构能够稳定地分隔不同腔室，在生产、运输、贮藏、销售等过程中的普通外力作用下仍保持结构稳定，从儿童到老人均可从外部容易地捏开，不需要特殊工具的辅助。捏开过程不破坏容器内部的密封环境，无菌环境得到保障，捏开后产生的极少量不溶性微粒也不会破坏药物质量。2. The virtual welding structure of the present invention can stably separate different chambers, and maintain structural stability under the action of common external forces during production, transportation, storage, and sales. It can be easily pinched open from the outside by everyone from children to the elderly without the assistance of special tools. The pinching process does not destroy the sealed environment inside the container, and the sterile environment is guaranteed. The very small amount of insoluble particles generated after pinching will not damage the quality of the drug.
3、本发明的容器整体体积小，装载总量约为20ml以下，主要用作滴眼液等使用体积较小的医用溶液的容器。本发明容器的装载量可以是单剂量，也可满足多剂量(通常不超过单月剂量)的要求。本发明容器的小剂量和良好的密封性使其在无需添加苯扎氯铵等抑菌剂的条件下，仍能符合药品的相关要求。从而避免了抑菌类物质对人体器官尤其是眼球等敏感器官的刺激性。 3. The container of the present invention has a small overall volume, and the total loading amount is about 20 ml or less, and is mainly used as a container for eye drops and other medical solutions with a small volume. The loading amount of the container of the present invention can be a single dose, and can also meet the requirements of multiple doses (usually not more than a single monthly dose). The small dose and good sealing performance of the container of the present invention make it still meet the relevant requirements of medicines without adding antibacterial agents such as benzalkonium chloride. Thereby avoiding the irritation of antibacterial substances to human organs, especially sensitive organs such as eyeballs.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1：为本申请中的多腔室滴眼液用容器的一个示例。FIG. 1 is an example of a multi-chamber eye drop container in the present application.
图中，1、容器本体；2、虚焊缝；3、第一腔室；4、第二腔室；5、流出口；6、封盖；7、容器尾部。In the figure, 1, container body; 2, virtual weld; 3, first chamber; 4, second chamber; 5, outflow port; 6, cover; 7, container tail.
具体实施方式DETAILED DESCRIPTION
下面将参照附图与具体实施方式对本发明的容器进行进一步的说明。给出的实施例仅为了阐明本发明，而不是为了限制本发明的范围。以下提供的实施例可作为本技术领域普通技术人员进行进一步改进的指南，并不以任何方式构成对本发明的限制。如本文中使用的，术语“包括”或“包含”意指结构及工艺包含所记载的组件或步骤，但不排除其它组件或步骤。如本文所用的，术语“约”是指为此技术领域中的技术人员容易知晓的相应值的常见误差范围。在本文中以“约”的方式描述的值或参数包含该值或参数本身。The container of the present invention will be further described below with reference to the accompanying drawings and specific embodiments. The examples given are only for illustrating the present invention, not for limiting the scope of the present invention. The examples provided below can be used as a guide for further improvements by those of ordinary skill in the art, and do not constitute a limitation of the present invention in any way. As used herein, the term "including" or "comprising" means that the structure and process include the components or steps described, but do not exclude other components or steps. As used herein, the term "approximately" refers to the common error range of the corresponding value that is easily known to those skilled in the art. The value or parameter described in this article in the form of "approximately" includes the value or parameter itself.
术语“多腔室”或“多个腔室”不仅包括具体实施例中示例的两个腔室的情况，也包括基于本发明所公开的内容和具体需求，本领域技术人员可以容易地想到的更多个腔室的情况，例如三个或更多个。The term "multi-chamber" or "multiple chambers" not only includes the case of two chambers illustrated in the specific embodiment, but also includes the case of more chambers that a person skilled in the art can easily think of based on the content disclosed in the present invention and specific needs, such as three or more.
术语“刚性塑料”在本文中是指能够因例如手指捏压施加的外力而发生形变、且在撤销外力后自动恢复初始形状的塑料。例如单剂量或多剂量眼药瓶所使用的常规塑料材质(参见《中国药典2015版》四部通则“9621药包材通用要求指导原则”；《国家药包材标准》，中国食品药品检定研究院组织编写，中国医药科技出版社)。换言之，用于制备本发明容器的塑料可以是任何本领域已知适合制备单剂量或多剂量医药溶液瓶的塑料，只要其所具有的弹性模量能够实现本发明的可逆形变和恢复即可。作为非限制性的示例，本发明所使用的刚性塑料可列举例如聚烯烃树脂，包括但不限于聚乙烯系树脂如低密度聚乙烯、聚丙烯系树脂如聚丙烯、环状聚烯烃树脂、以及包含不同的上述聚烯烃的复合层材料等。本发明所使用的刚性塑料还可参见例如齐贵亮等编著《常用塑料品种速查手册》。作为本发明中的“刚性塑料”的非限制性实例，还可以参见由申请人于本申请的申请日同日提交的、名为“一种低浓度的阿托品药物产品及其制造方法”的发明专利申请中记载的示例。该同日申请通过引用全文并入本申请中。 The term "rigid plastic" in this article refers to a plastic that can be deformed due to an external force applied by, for example, finger pinching, and automatically restores its original shape after the external force is removed. For example, conventional plastic materials used in single-dose or multi-dose eye drops bottles (see the "9621 General Requirements and Guidelines for Drug Packaging Materials" in the four general rules of the "Chinese Pharmacopoeia 2015 Edition";"National Drug Packaging Material Standards", organized and compiled by the China Food and Drug Inspection Institute, China Medical Science and Technology Press). In other words, the plastic used to prepare the container of the present invention can be any plastic known in the art that is suitable for preparing single-dose or multi-dose medical solution bottles, as long as the elastic modulus it has can achieve the reversible deformation and recovery of the present invention. As a non-limiting example, the rigid plastic used in the present invention can be listed as polyolefin resins, including but not limited to polyethylene resins such as low-density polyethylene, polypropylene resins such as polypropylene, cyclic polyolefin resins, and composite layer materials containing different polyolefins. The rigid plastic used in the present invention can also be found in, for example, the "Quick Reference Manual for Common Plastic Varieties" compiled by Qi Guiliang et al. As a non-limiting example of "rigid plastic" in the present invention, reference may also be made to the examples described in the invention patent application entitled "A low-concentration atropine drug product and a method for manufacturing the same" filed by the applicant on the same date as the filing date of the present application. The entire text of the application on the same date is incorporated into the present application by reference.
在本发明的一个方面，本发明容器中所使用的刚性塑料的厚度既能实现本发明容器所需的可逆形变和恢复，又具有医药容器(尤其是滴眼液容器)所需的机械强度。在优选的实施方案中，本发明容器中所使用的刚性塑料具有厚度为200～2000μm，优选350～500μm，更优选380～400μm。在需要对氧气、水蒸气、光照等进行阻挡的情况下，用于本发明容器的树脂也可以层合有铝箔等金属材质。在此情况下，本发明容器的刚性塑料的厚度为包含全部层合材料之后的厚度。In one aspect of the present invention, the thickness of the rigid plastic used in the container of the present invention can achieve the reversible deformation and recovery required by the container of the present invention, and has the mechanical strength required by the medical container (especially the eye drop container). In a preferred embodiment, the rigid plastic used in the container of the present invention has a thickness of 200 to 2000 μm, preferably 350 to 500 μm, and more preferably 380 to 400 μm. In the case where it is necessary to block oxygen, water vapor, light, etc., the resin used in the container of the present invention can also be laminated with a metal material such as aluminum foil. In this case, the thickness of the rigid plastic of the container of the present invention is the thickness after including all the laminated materials.
在本发明的一个方面，本发明的容器可以是任何合适的形状，只要其适合容纳单剂量或多剂量的医药溶液即可。在优选的实施方案中，本发明的容器由具有一定长度和直径的管状刚性塑料制成。在本文中，“管状”是指具有一定长度的中空柱状结构。在一些实施方案中，管状的长度显著大于其直径。在优选的实施方案中，管状具有15～180mm的长度、4～30mm的内直径。In one aspect of the invention, the container of the present invention can be any suitable shape, as long as it is suitable for accommodating single-dose or multi-dose pharmaceutical solutions. In a preferred embodiment, the container of the present invention is made of tubular rigid plastics with a certain length and diameter. In this article, "tubular" refers to a hollow cylindrical structure with a certain length. In some embodiments, the length of the tubular is significantly greater than its diameter. In a preferred embodiment, the tubular has a length of 15 to 180 mm and an inner diameter of 4 to 30 mm.
在本发明的一个方面，本发明的容器具有适合容纳单剂量或多剂量的医药溶液的容量。在本文中，“容量”是指容器包含的所有腔室能够容纳的溶液体积的总和。在一些实施方案中，本发明的容器具有0.2ml以上且20ml以下的容量。In one aspect of the invention, the container of the present invention has a capacity suitable for holding a single dose or multiple doses of a pharmaceutical solution. In this article, "capacity" refers to the sum of the volume of solutions that all chambers included in the container can hold. In some embodiments, the container of the present invention has a capacity of more than 0.2 ml and less than 20 ml.
其中，容量和管材尺寸的大致对应关系如下所示：
Among them, the approximate correspondence between capacity and pipe size is as follows:
在本发明的一个方面，术语“可脱开的密封部件”与“虚焊缝”可互换的使用，是指主要由本发明的容器本体经虚焊工艺所形成的结构，该结构能够隔离本发明容器的不同腔室、且在一定作用力下可剥离或脱开。本发明容器的虚焊缝可适用任何设计，只要其能够由于使用者出于使用目的施加在任一腔室壁上的压力而容易地脱开，同时不会受到制剂、包装、运输、销售等过程中的正常外力而出现非期望的脱开即可。在一些实施方案中，虚焊缝可以呈狭长的直线状结构。在另一些实施方案中，虚焊缝也可以呈带有弯曲的弧线状或者带有夹角的相交直线状。在一些实施方案中，虚焊缝具有均匀的相等宽度。在另一些实施方案中，虚焊缝具有可变的宽度。在优选的实施方案中，虚焊缝的宽度为1～20mm，优选2～8mm，更优选4mm。 In one aspect of the present invention, the term "detachable sealing member" and "virtual weld" are used interchangeably, and refer to a structure mainly formed by the container body of the present invention through a virtual welding process, which can isolate different chambers of the container of the present invention and can be peeled or detached under a certain force. The virtual weld of the container of the present invention can be applied to any design, as long as it can be easily detached due to the pressure applied by the user on any chamber wall for the purpose of use, and will not be undesirably detached due to normal external forces during the preparation, packaging, transportation, sales, etc. In some embodiments, the virtual weld can be a narrow and long straight-line structure. In other embodiments, the virtual weld can also be in the shape of a curved arc or an intersecting straight line with an angle. In some embodiments, the virtual weld has a uniform and equal width. In other embodiments, the virtual weld has a variable width. In a preferred embodiment, the width of the virtual weld is 1 to 20 mm, preferably 2 to 8 mm, and more preferably 4 mm.
在本发明的一个方面，本发明容器的多个腔室中分别填充不同的医用溶液。例如，在本发明容器为两个腔室的情况下，可以在第一腔室中填充易于水解的药物，在第二腔室中填充制药上可接受的辅料成分的水溶液。作为非限制性的示例，可以填充在第一腔室中的药物可列举盐酸丁卡因、盐酸可卡因、普鲁本辛、硫酸阿托品、氢溴酸后马托品等酯类药物、酰胺类药物等。可以填充在第二腔室中的药物的非限制性示例包括但不限于缓冲盐、渗透压调节剂、防腐剂和/或金属离子螯合剂等。本领域技术人员可以理解的是，本发明容器的腔室中的内容物是可以改变的，例如，可以将两个腔室内的溶液分别替换为其他适合的溶液，只要其最终能够混合形成可直接施用于眼部的滴眼液即可。例如，可以将第一腔室中的酯类药物替换为例如硝酸毛果芸香碱，华法林钠等内酯类药物。在本发明的其他方面，填充溶液对容器腔室的指派也是可以改变的，即，可在第一腔室中包含缓冲液等制药上可接受的辅料的水溶液，而在第二腔室中包含易水解的药物溶液。在本发明的其他方面，使用者应当在即将施用前将这两种溶液均匀地混合在一起，形成用于直接向眼部施用的滴眼液。In one aspect of the present invention, different medical solutions are filled in the multiple chambers of the container of the present invention. For example, in the case where the container of the present invention has two chambers, a drug that is easily hydrolyzed can be filled in the first chamber, and an aqueous solution of a pharmaceutically acceptable excipient component can be filled in the second chamber. As a non-limiting example, the drugs that can be filled in the first chamber can include ester drugs such as tetracaine hydrochloride, cocaine hydrochloride, propantheline, atropine sulfate, and homatropine hydrobromide, amide drugs, etc. Non-limiting examples of drugs that can be filled in the second chamber include but are not limited to buffer salts, osmotic pressure regulators, preservatives and/or metal ion chelators, etc. It can be understood by those skilled in the art that the contents in the chambers of the container of the present invention can be changed, for example, the solutions in the two chambers can be replaced with other suitable solutions, as long as they can eventually be mixed to form eye drops that can be directly applied to the eyes. For example, the ester drugs in the first chamber can be replaced with lactone drugs such as pilocarpine nitrate and warfarin sodium. In other aspects of the present invention, the assignment of the filling solution to the container chamber can also be changed, that is, an aqueous solution of a pharmaceutically acceptable excipient such as a buffer solution can be contained in the first chamber, and a readily hydrolyzable drug solution can be contained in the second chamber. In other aspects of the present invention, the user should evenly mix the two solutions together just before administration to form an eye drop for direct administration to the eye.
在本发明的一个方面，本发明容器所使用的流出口和封盖可以采用本领域常规使用的任何流出口和封盖结构，只要在打开封盖的情况下允许位于该容器中的溶液以逐滴的方式挤出该容器即可。在本发明的其他方面，本发明容器的流出口也可以是无需加盖的封闭端口，只要其在使用时能够容易的打开即可。在本发明的其他方面，本发明容器的流出口还可以是能够重复开启和关闭的、且与多腔室容器本体相连接或相脱离的封盖。In one aspect of the present invention, the outflow port and the cover used in the container of the present invention can adopt any outflow port and cover structure conventionally used in the art, as long as the solution in the container is allowed to be squeezed out of the container in a dropwise manner when the cover is opened. In other aspects of the present invention, the outflow port of the container of the present invention can also be a closed port that does not need to be covered, as long as it can be easily opened when in use. In other aspects of the present invention, the outflow port of the container of the present invention can also be a cover that can be repeatedly opened and closed and connected to or disconnected from the multi-chamber container body.
在本发明的一个方面，虚焊的位置可以根据所注入的目标溶液的量容易地确定。例如，当注入的两种目标溶液为等量时，在容器本体的临近中点处进行虚焊。在具体的实施方案中，用于虚焊本发明容器的工艺优选使用超声波焊接，但也可以选择其它合适的焊接方式。作为虚焊的非限制性示例，可列举使用具有型号为LEYH32NZC-50M的电动执行器的超声波焊接机(型号STD20-1500W)，或者使用具有型号为EDG-2020的超声波发生器的超声波焊接机进行。In one aspect of the present invention, the position of the virtual welding can be easily determined according to the amount of the target solution injected. For example, when the two target solutions injected are equal, the virtual welding is performed near the midpoint of the container body. In a specific embodiment, the process for virtual welding the container of the present invention preferably uses ultrasonic welding, but other suitable welding methods can also be selected. As a non-limiting example of virtual welding, an ultrasonic welding machine (model STD20-1500W) with an electric actuator of model LEYH32NZC-50M can be cited, or an ultrasonic welding machine with an ultrasonic generator of model EDG-2020 can be used.
在本发明的一个方面，用于封接尾部的工艺为本领域通常用于塑料材质焊接的工艺，包括但不限于热熔接、超声波焊接等。在本发明的优选方面，使用超声波焊接进行本发明容器的尾封。作为封接尾部的非限制性示例，可列举使用具有型号为MD81840-50Z的气缸的超声波焊接机(型号STD-2000W)，或者使用具有型号为 EDG-2020的超声波发生器的超声波焊接机进行。In one aspect of the present invention, the process used to seal the tail is a process commonly used in the art for welding plastic materials, including but not limited to heat fusion welding, ultrasonic welding, etc. In a preferred aspect of the present invention, ultrasonic welding is used to seal the tail of the container of the present invention. As a non-limiting example of sealing the tail, an ultrasonic welding machine (model STD-2000W) with a cylinder model MD81840-50Z or a The ultrasonic welding machine is carried out by the ultrasonic generator of EDG-2020.
下述实施例中类似或者相同的部件将使用相同的附图标记指代，并且将不再进行重复性说明。Similar or identical components in the following embodiments will be denoted by the same reference numerals, and will not be described repeatedly.
实施例1：容器的结构、组成和使用方式Example 1: Structure, composition and use of container
图1示出了本申请的一个具体实施例。FIG1 shows a specific embodiment of the present application.
多腔室容器的本体1包括第一腔室3和第二腔室4。第一腔室3和第二腔室4之间为密封部分2(即虚焊缝)。The body 1 of the multi-chamber container comprises a first chamber 3 and a second chamber 4. A sealing portion 2 (ie, a virtual weld) is provided between the first chamber 3 and the second chamber 4.
容器本体1的材质为聚烯烃树脂，其允许使用超声波工艺进行虚焊，兼具透明性、卫生性和适当的弹性和刚性。The container body 1 is made of polyolefin resin, which allows cold welding using ultrasonic technology and has transparency, hygiene, and appropriate elasticity and rigidity.
施用时，无需任何特定的辅助装置，通过例如单手手动施压的方式使第一腔室3或者第二腔室4受压而腔室的内部压力增加，即可使得虚焊缝打开，进而使第一腔室3和第二腔室4相互连通，两个腔室中收纳的药剂溶液混合在一起。并且，通过手动施压方式不会使得该多腔室容器的尾部7破损，不会导致容器内容物从尾部不理想地流出。接着，扭断去除流出口5前端的封盖6，使流出口5处于开启状态，所形成的混合溶液能够以逐滴的方式从流出口5被挤出。During application, no special auxiliary device is required. For example, by manually applying pressure with one hand, the first chamber 3 or the second chamber 4 is pressurized and the internal pressure of the chamber is increased, so that the virtual weld can be opened, and the first chamber 3 and the second chamber 4 are connected to each other, and the pharmaceutical solutions contained in the two chambers are mixed together. In addition, the tail 7 of the multi-chamber container will not be damaged by manually applying pressure, and the contents of the container will not flow out of the tail undesirably. Then, the cover 6 at the front end of the outflow port 5 is twisted off and removed, so that the outflow port 5 is in an open state, and the formed mixed solution can be squeezed out from the outflow port 5 in a drop-by-drop manner.
实施例2：多腔室滴眼液制品的制备Example 2: Preparation of multi-chamber eye drop product
本发明的多腔室滴眼液制品可利用如下工艺制成。The multi-chamber eye drop product of the present invention can be made by the following process.
使用直径为13.0mm(±0.2mm)、两端开口的低密度聚乙烯(LDPE)软管来制备双腔容器的本体。The body of the double-chamber container was prepared using a low-density polyethylene (LDPE) hose with a diameter of 13.0 mm (±0.2 mm) and open ends.
先将所述聚烯烃软管依次截短形成长度一致的短管，具体长度可以根据计划装载的药量适当调整，一般不小于约40mm。本实施例中，软管截短为40mm长度。First, the polyolefin hose is shortened in sequence to form a short tube with the same length. The specific length can be adjusted appropriately according to the planned amount of medicine to be loaded, and is generally not less than about 40 mm. In this embodiment, the hose is shortened to a length of 40 mm.
然后，采用常规吹塑工艺在截短软管的一端形成流出口5，流出口与容器本体中的腔室连通。该容器还配有适合所述流出口5的封盖6，用于封闭流出口。Then, a conventional blow molding process is adopted to form a flow outlet 5 at one end of the shortened hose, and the flow outlet is communicated with the chamber in the container body. The container is also provided with a cover 6 suitable for the flow outlet 5 for closing the flow outlet.
自软管未形成流出口的另一端向容器本体1中注入第一药剂溶液。然后，使用具有型号为LEYH32NZC-50M的电动执行器的型号为STD20-1500W的超声波焊接机在容器本体1的长度中点处进行超声波虚焊，焊接时间为0.290～0.370s。The first drug solution was injected into the container body 1 from the other end of the hose where no outflow port was formed. Then, ultrasonic welding was performed at the midpoint of the length of the container body 1 using an ultrasonic welding machine of model STD20-1500W with an electric actuator of model LEYH32NZC-50M, and the welding time was 0.290 to 0.370 s.
虚焊后，容器本体1形成两个相互不连通的腔室，即具备流出口5的第一腔室3和远离流出口5而与第一腔室3通过虚焊连接的第二腔室4，其中第一腔室3中已经装填第一种药剂溶液，另一个为仍未收纳溶液的空心结构。After cold welding, the container body 1 forms two chambers that are not connected to each other, namely, a first chamber 3 with an outflow port 5 and a second chamber 4 away from the outflow port 5 and connected to the first chamber 3 by cold welding, wherein the first chamber 3 has been filled with the first pharmaceutical solution, and the other is a hollow structure that has not yet received the solution.
自上述空心结构的开口处继续将第二种药剂溶液填充至容器本体1中，然后使 用具有型号为MD81840-50Z的气缸的型号为STD-2000W的超声波焊接机焊接，以封闭所述开口形成容器尾部7，从而构成装填有第二种药剂溶液的封闭的第二腔室4。Continue to fill the second pharmaceutical solution into the container body 1 from the opening of the hollow structure, and then The opening is welded by using an ultrasonic welding machine of model STD-2000W with a cylinder of model MD81840-50Z to close the opening to form a container tail 7, thereby forming a closed second chamber 4 filled with a second pharmaceutical solution.
本实施例测试了采用气缸气压为1.7～2.5bar、焊接时间为0.16～0.22s的不同制备参数封接形成容器尾部时的完整封合率。结果示于下表A)中。This embodiment tests the complete sealing rate when the container tail is sealed using different preparation parameters with cylinder pressure of 1.7-2.5 bar and welding time of 0.16-0.22 s. The results are shown in the following table A).
A)用于封接形成尾部的参数
A) Parameters used to seal the tail
本实施例测试了采用电缸扭力力度为232～266N、焊接时间为0.200～0.370s的不同制备参数封接形成容器虚焊缝时的完整封合率和捏开率。根据常规仪器测量，结果示于下表B)中。This embodiment tests the complete sealing rate and pinching rate when different preparation parameters are used to seal the container virtual weld seam with the electric cylinder torque of 232-266N and welding time of 0.200-0.370s. The results are shown in the following table B) according to conventional instrument measurement.
表B)用于形成虚焊缝的参数

Table B) Parameters for forming virtual welds

在模拟日常使用的条件下，由儿童(平均年龄7岁)、青年(平均年龄28岁)和老年人(平均年龄60岁)各6名，分别各对15个滴眼液瓶独立进行捏开。测定每名受试者完全捏开滴眼液瓶虚焊缝所需时间的平均值，示出于下表C)中。表中，组A代表以焊接时间0.345s、气缸扭力力度238.6N进行虚焊；组B代表以焊接时间0.305s、气缸扭力力度241N进行虚焊。Under conditions simulating daily use, 6 children (average age 7 years old), 6 young people (average age 28 years old) and 6 elderly people (average age 60 years old) each independently pinched open 15 eye drop bottles. The average time required for each subject to completely pinch open the virtual weld of the eye drop bottle was measured and shown in the following table C). In the table, group A represents a virtual weld with a welding time of 0.345s and a cylinder torque of 238.6N; group B represents a virtual weld with a welding time of 0.305s and a cylinder torque of 241N.
表C)捏开试验
Table C) Pinch test
由表C可见，改变虚焊条件在一定程度上会影响受试者捏开本发明容器所需的时间。但总体而言，本发明双腔容器的虚焊缝能够被未经专业训练的普通使用者容易地打开，以便于进行后续的滴眼操作。并且，即使是精细操作能力和捏合力较弱的儿童与老年人也均能容易且迅速地完成对本发明容器的捏开操作。 As can be seen from Table C, changing the virtual welding conditions will affect the time required for the subject to pinch open the container of the present invention to a certain extent. But in general, the virtual welding seam of the double-chamber container of the present invention can be easily opened by ordinary users without professional training, so as to facilitate the subsequent eye drop operation. Moreover, even children and the elderly with weak fine operation ability and pinching force can easily and quickly complete the pinching operation of the container of the present invention.
实施例3：多腔室滴眼液制品的制备Example 3: Preparation of multi-chamber eye drop product
本发明的多腔室滴眼液制品还可利用如下工艺制成。The multi-chamber eye drop product of the present invention can also be made by the following process.
按照与实施例2相同的步骤，依次对聚烯烃软管进行流出口成型、填充第一溶液、虚焊、填充第二溶液、封尾。其中，不同于实施例2，本实施例使用的聚烯烃软管为聚丙烯软管，并且通过改变超声波发生器(型号为EDG-2020)的振幅和焊接时间，使用同一台超声波焊接设备完成了虚焊和尾部封接。According to the same steps as in Example 2, the polyolefin hose is sequentially subjected to outlet molding, filling with the first solution, virtual welding, filling with the second solution, and tail sealing. Unlike Example 2, the polyolefin hose used in this example is a polypropylene hose, and the virtual welding and tail sealing are completed using the same ultrasonic welding equipment by changing the amplitude and welding time of the ultrasonic generator (model EDG-2020).
本实施例测试了采用振幅为10～45％、焊接时间为0.19～0.95s的不同制备参数封接形成容器尾部时的完整封合率。结果示于下表D)中。This embodiment tests the complete sealing rate when the container tail is sealed using different preparation parameters with an amplitude of 10-45% and a welding time of 0.19-0.95s. The results are shown in the following table D).
D)用于封接形成尾部的参数
D) Parameters used to seal the tail
本实施例测试了采用振幅为10～45％、焊接时间为0.19～1.10s的不同制备参数封接形成容器虚焊缝时的完整封合率和捏开率。根据常规仪器测量，结果示于下表E)中。This example tests the complete sealing rate and pinching rate when different preparation parameters are used to seal and form a container virtual weld seam with an amplitude of 10-45% and a welding time of 0.19-1.10s. The results are shown in the following table E) according to conventional instrument measurements.
表E)用于形成虚焊缝的参数

Table E) Parameters for forming virtual welds

在模拟日常使用的条件下，由儿童(平均年龄7岁)、青年(平均年龄28岁)和老年人(平均年龄60岁)各6名，分别各对15个滴眼液瓶独立进行捏开。测定每名受试者完全捏开滴眼液瓶虚焊缝所需时间的平均值，示出于下表F)中。表中，组A代表以焊接时间0.47s，振幅39％进行虚焊；组B代表以焊接时间0.49s，振幅36％进行虚焊。Under conditions simulating daily use, 6 children (average age 7 years old), 6 young people (average age 28 years old) and 6 elderly people (average age 60 years old) each independently pinched open 15 eye drop bottles. The average time required for each subject to completely pinch open the virtual weld of the eye drop bottle was measured and shown in the following Table F). In the table, Group A represents a virtual weld with a welding time of 0.47s and an amplitude of 39%; Group B represents a virtual weld with a welding time of 0.49s and an amplitude of 36%.
表F-1)捏开试验

Table F-1) Pinch test

由表F可见，改变虚焊条件在一定程度上会影响受试者捏开本发明容器所需的时间。但总体而言，本发明双腔容器的虚焊缝能够被未经专业训练的普通使用者容易地打开。As can be seen from Table F, changing the virtual welding conditions will affect the time required for the subject to pinch open the container of the present invention to a certain extent. But in general, the virtual welding seam of the double-chamber container of the present invention can be easily opened by ordinary users without professional training.
实施例4：不溶性微粒测定Example 4: Determination of insoluble particles
作为收纳在两个腔室中的药液的举例，本发明使用了如下的药液组合物，用于测定捏开虚焊缝混合后混合溶液中的不溶性微粒状况：As an example of the liquid contained in the two chambers, the present invention uses the following liquid composition to measure the insoluble particles in the mixed solution after pinching the virtual weld seam and mixing:
组合物1：Composition 1:
第一溶液：First solution:
盐酸丁卡因、盐酸可卡因、普鲁本辛等0.01～0.05％；Tetracaine hydrochloride, cocaine hydrochloride, propantheline, etc. 0.01-0.05%;
磷酸二氢钠0.01～0.09％；Sodium dihydrogen phosphate 0.01～0.09%;
磷酸氢二钠0.01～0.45％；Disodium hydrogen phosphate 0.01～0.45%;
氯化钠0～0.9％；Sodium chloride 0～0.9%;
余量为水；The balance is water;
pH调节为3.5-4.5。The pH was adjusted to 3.5-4.5.
第二溶液：Second solution:
磷酸二氢钠0～0.09％；Sodium dihydrogen phosphate 0～0.09%;
磷酸氢二钠0～0.45％；Disodium hydrogen phosphate 0～0.45%;
氯化钠0～0.9％；Sodium chloride 0～0.9%;
依地酸二钠0～0.1％；Edetate disodium 0-0.1%;
pH调节为7.0～8.5。The pH was adjusted to 7.0-8.5.
组合物2：Composition 2:
第一溶液：First solution:
硝酸毛果芸香碱1％-2％、华法林钠等；Pilocarpine nitrate 1%-2%, warfarin sodium, etc.
枸橼酸钠水合物0.1～0.20％；Sodium citrate hydrate 0.1-0.20%;
硼酸0.5～1.0％； Boric acid 0.5-1.0%;
氯化钠0～0.9％；Sodium chloride 0～0.9%;
余量为水；The balance is water;
pH调节为3～4。The pH was adjusted to 3-4.
第二溶液：Second solution:
枸橼酸钠水合物0.5～1.0％；Sodium citrate hydrate 0.5-1.0%;
氯化钠0～0.9％；Sodium chloride 0～0.9%;
苯扎氯铵0～0.1％；Benzalkonium chloride 0-0.1%;
pH调节为7～8。The pH was adjusted to 7-8.
根据《药典》所规定不溶性微粒测量方法，分别测定纯水、收纳于经过封尾工艺而制备的单腔容器、以及通过本发明的优选工艺(使用具有型号为LEYH32NZC-50M的电动执行器的型号为STD20-1500W的超声波焊接机进行虚焊，焊接时间0.305s，电缸扭力力度241N)制备的双腔容器中的眼用溶液所含的不溶性微粒数量。测量结果示于下表G)中。According to the insoluble particle measurement method specified in the Pharmacopoeia, the amount of insoluble particles contained in the ophthalmic solution in pure water, in a single-chamber container prepared by the tail-sealing process, and in a double-chamber container prepared by the preferred process of the present invention (using an ultrasonic welding machine of model STD20-1500W with an electric actuator of model LEYH32NZC-50M for cold welding, welding time 0.305s, electric cylinder torque strength 241N) was measured. The measurement results are shown in the following Table G).
表G)不溶性微粒测定结果
Table G) Insoluble particles determination results
结果显示，本发明工艺对容器所含溶液中的不溶性微粒数量的影响主要体现在10μm及10μm以上的微粒，而对溶液中25μm及25μm以上的微粒含量的影响不具有统计学显著性。并且，即使是对于10μm及10μm以上的微粒，使用本发明工艺所制备的容器仍然符合药典等的强制性规定。The results show that the effect of the process of the present invention on the number of insoluble particles in the solution contained in the container is mainly reflected in particles of 10 μm and above, while the effect on the content of particles of 25 μm and above in the solution is not statistically significant. Moreover, even for particles of 10 μm and above, the container prepared by the process of the present invention still meets the mandatory provisions of the pharmacopoeia and the like.
以上对本发明进行了详述。对于本领域技术人员来说，在不脱离本发明的宗旨和范围，以及无需进行不必要的实验情况下，可在等同参数、浓度和条件下，在较宽范围内实施本发明。虽然本发明给出了特殊的实施例，应该理解为，可以对本发明作进一步的改进。总之，按本发明的原理，本申请欲包括任何变更、用途或对本发明的改进，包括脱离了本申请中已公开范围，而用本领域已知的常规技术进行的改变。按以下附带的权利要求的范围，可以进行一些基本特征的应用。 The present invention has been described in detail above. It will be apparent to those skilled in the art that the present invention may be implemented in a wide range under equivalent parameters, concentrations and conditions without departing from the spirit and scope of the present invention and without the need for unnecessary experimentation. Although the present invention provides specific embodiments, it should be understood that further improvements may be made to the present invention. In short, according to the principles of the present invention, this application is intended to include any changes, uses or improvements to the present invention, including changes made by conventional techniques known in the art that depart from the scope disclosed in this application. Applications of some of the basic features may be made within the scope of the following appended claims.

Claims (14)

  1. 一种滴眼液用多腔室容器，其特征在于，所述容器的本体(1)由至少包括第一腔室(3)和第二腔室(4)在内的两个以上的药剂收纳腔室组成，所述第一腔室(3)与流出口(5)连通，其余腔室与第一腔室或其它腔室连接，相邻的腔室被密封部分(2)所分隔而互不连通；其中，在对相邻的两个腔室之一的外壁施加外力的条件下，将导致该相邻的两个腔室之间的所述密封部分不可逆地脱开，全部密封部分均脱开时，每个腔室都将直接或间接与第一腔室连接。A multi-chamber container for eye drops, characterized in that the body (1) of the container is composed of at least two medicine storage chambers including a first chamber (3) and a second chamber (4), the first chamber (3) is connected to an outflow port (5), and the remaining chambers are connected to the first chamber or other chambers, and adjacent chambers are separated by a sealing part (2) and are not connected to each other; wherein, when an external force is applied to the outer wall of one of the two adjacent chambers, the sealing part between the two adjacent chambers will be irreversibly detached, and when all the sealing parts are detached, each chamber will be directly or indirectly connected to the first chamber.
  2. 权利要求1所述的多腔室容器，其特征在于，所述流出口(5)上还设置有封盖(6)，该封盖(6)为一次性开启的或者为可重复启闭的。The multi-chamber container according to claim 1 is characterized in that a sealing cover (6) is also provided on the outflow port (5), and the sealing cover (6) can be opened once or can be opened and closed repeatedly.
  3. 前述权利要求任一项所述的多腔室容器，其特征在于，所述容器本体的材质为刚性塑料，优选地，所述刚性塑料的厚度为200～2000μm，优选350～500μm，更优选380～400μm。The multi-chamber container according to any one of the preceding claims is characterized in that the material of the container body is rigid plastic, preferably, the thickness of the rigid plastic is 200-2000 μm, preferably 350-500 μm, and more preferably 380-400 μm.
  4. 前述权利要求任一项所述的多腔室容器，其特征在于，所述多腔室容器由两个腔室构成。The multi-chamber container according to any one of the preceding claims, characterized in that the multi-chamber container consists of two chambers.
  5. 前述权利要求任一项所述的多腔室容器，其特征在于，所述密封部分是使用电缸扭力力度为232～266牛、焊接时间为0.290～0.370s的超声波将所述容器本体虚焊在一起而形成的；The multi-chamber container according to any one of the preceding claims, characterized in that the sealing portion is formed by using ultrasonic welding of the container body with an electric cylinder torque of 232 to 266 Newtons and a welding time of 0.290 to 0.370 seconds;
    可选地，所述密封部分是使用振幅为10％～42％、焊接时间为0.19～0.64s的超声波，优选振幅为36％～39％、焊接时间为0.47～0.49s的超声波将所述容器本体虚焊在一起而形成的。Optionally, the sealing portion is formed by cold welding the container body together using ultrasonic waves with an amplitude of 10% to 42% and a welding time of 0.19 to 0.64 s, preferably ultrasonic waves with an amplitude of 36% to 39% and a welding time of 0.47 to 0.49 s.
  6. 前述权利要求任一项所述的多腔室容器，其特征在于，所述能够使密封部分不可逆脱开的外力为不超过5～7岁儿童手指的平均捏合力，优选不超过17～27牛顿(N)。The multi-chamber container according to any one of the preceding claims is characterized in that the external force capable of irreversibly disengaging the sealing portion is no more than the average pinching force of a 5-7 year old child's fingers, preferably no more than 17-27 Newtons (N).
  7. 前述权利要求任一项所述的多腔室容器，其特征在于，所述容器还包含容器尾部(7)，所述尾部是在气缸气压为2.0～2.5bar、焊接时间为0.16～0.22s的封接条件下形成的；可选地，所述容器还包含容器尾部(7)，所述尾部是在超声波振幅为43％以上、焊接时间为0.65s以上的封接条件下形成的。The multi-chamber container according to any of the preceding claims is characterized in that the container further comprises a container tail (7), which is formed under sealing conditions of a cylinder pressure of 2.0 to 2.5 bar and a welding time of 0.16 to 0.22 s; optionally, the container further comprises a container tail (7), which is formed under sealing conditions of an ultrasonic amplitude of more than 43% and a welding time of more than 0.65 s.
  8. 前述权利要求任一项所述的多腔室容器，其特征在于，所述容器的本体为管状；优选地，所述管状具有15～180mm的长度、4～30mm的内直径。The multi-chamber container according to any one of the preceding claims is characterized in that the body of the container is tubular; preferably, the tubular shape has a length of 15 to 180 mm and an inner diameter of 4 to 30 mm.
  9. 前述权利要求任一项所述的多腔室容器，其具有0.2ml以上且20ml以下的容量。 The multi-chamber container according to any one of the preceding claims, having a capacity of 0.2 ml or more and 20 ml or less.
  10. 前述权利要求任一项所述的多腔室容器，其特征在于，所述密封部分呈狭长的直线状结构或呈带有弯曲的弧线状或者带有夹角的相交直线状；可选地，所述密封部分具有均匀的相等宽度或具有可变的宽度；优选地，所述密封部分宽度为1～20mm，优选2～8mm，更优选4mm。The multi-chamber container according to any of the preceding claims is characterized in that the sealing portion is in the form of a long and narrow straight line structure or in the form of a curved arc or an intersecting straight line with an angle; optionally, the sealing portion has a uniform equal width or a variable width; preferably, the sealing portion has a width of 1 to 20 mm, preferably 2 to 8 mm, and more preferably 4 mm.
  11. 一种在前述权利要求任一项所述多腔室容器的多个腔室中分别装填有不同药剂的滴眼液制品，其中所述药剂中的至少一种具有低于5.3或高于8.3的pH值，装填在多个腔室中的药剂混合所形成的混合溶液则具有5.3至8.3的pH值，且至少一种药剂的稳定性高于装填在不同腔室中的药剂混合后所形成的混合溶液的稳定性。An eye drop product in which different medicaments are respectively filled in the multiple chambers of the multi-chamber container according to any one of the preceding claims, wherein at least one of the medicaments has a pH value lower than 5.3 or higher than 8.3, and a mixed solution formed by mixing the medicaments filled in the multiple chambers has a pH value of 5.3 to 8.3, and the stability of at least one medicament is higher than the stability of the mixed solution formed by mixing the medicaments filled in different chambers.
  12. 一种用于制备权利要求11所述滴眼液制品的方法，所述方法包括：A method for preparing the eye drop preparation according to claim 11, the method comprising:
    选择适宜制成容器的本体(1)的材质，所述材质具有两端或多端开口的空心结构；Selecting a material suitable for making the body (1) of the container, wherein the material has a hollow structure with two or more ends open;
    在所述空心结构的一端开口形成一个流出口(5)，并优选在流出口(5)上设置有封盖(6)，该封盖(6)为一次性开启的或者为可重复启闭的，所述流出口(5)与第一腔室(3)连通；An outlet (5) is formed at one end of the hollow structure, and a cover (6) is preferably provided on the outlet (5), the cover (6) being disposable or re-openable and re-closable, and the outlet (5) is in communication with the first chamber (3);
    在所述流出口(5)处于封闭状态的情况下，在其它端开口向所述空心结构中填充第一指定体积的第一药剂；When the outflow port (5) is in a closed state, the first end opening is used to fill the first specified volume of the first medicament into the hollow structure;
    在所述空心结构的与所述第一指定体积相对应的位置处进行虚焊，形成可脱开的密封部分(2)，从而在所述可脱开的密封部分(2)与所述流出口(5)之间形成内部含有所述第一药剂的、密封的第一腔室(3)；Performing cold welding at a position of the hollow structure corresponding to the first designated volume to form a detachable sealing portion (2), thereby forming a sealed first chamber (3) containing the first medicament between the detachable sealing portion (2) and the outflow port (5);
    自其它端开口将第二指定体积的第二药剂继续填充至该开口与可脱开的密封部分(2)之间形成的第二腔室(4)，所述第二药剂不同于所述第一药剂；Continue filling a second prescribed volume of a second medicine into a second chamber (4) formed between the other end opening and the releasable sealing portion (2), wherein the second medicine is different from the first medicine;
    以此类推，任选形成通过密封部分相互分隔的装填有更多不同药剂的更多腔室；By analogy, more chambers filled with more different medicines separated from each other by sealing portions are optionally formed;
    在将最后一种药剂装填至最后一个腔室之后，通过焊接密封该最后一个腔室形成所述容器的尾部(7)；After the last medicine is filled into the last chamber, the last chamber is sealed by welding to form the tail portion (7) of the container;
    如此，各腔室中装填的各种药剂最终均可通过脱开各密封部分而直接或间接与第一腔室(3)中的药剂混合，从而自流出口(5)排出。In this way, the various medicines filled in the various chambers can eventually be directly or indirectly mixed with the medicine in the first chamber (3) by releasing the various sealing parts, and then discharged from the outflow port (5).
  13. 权利要求12所述制备滴眼液制品的方法，其中通过使用电缸扭力力度为232～266牛、焊接时间为0.290～0.370s的超声波进行虚焊以形成所述每个密封部分(2)，并使用气缸压力为2.0～2.5bar、焊接时间为0.16～0.22s的超声波焊接密封最 后一个腔室以形成所述容器的尾部(7)；The method for preparing an eye drop product according to claim 12, wherein each sealing portion (2) is formed by using an ultrasonic welding method with an electric cylinder torque of 232 to 266 Newtons and a welding time of 0.290 to 0.370 seconds, and an ultrasonic welding method with a cylinder pressure of 2.0 to 2.5 bar and a welding time of 0.16 to 0.22 seconds is used to seal the most A rear chamber to form a tail portion (7) of the container;
    可选地，其中通过使用振幅为10％～42％、焊接时间为0.19～0.64s的超声波，优选振幅为36％～39％、焊接时间为0.47～0.49s的超声波进行虚焊以形成所述每个密封部分(2)，并在振幅为43％以上、焊接时间为0.65s以上的封接条件下焊接密封最后一个腔室以形成所述容器的尾部(7)。Optionally, each sealing portion (2) is formed by performing cold welding using ultrasonic waves with an amplitude of 10% to 42% and a welding time of 0.19 to 0.64 s, preferably an amplitude of 36% to 39% and a welding time of 0.47 to 0.49 s, and the last chamber is welded and sealed under the sealing conditions of an amplitude of more than 43% and a welding time of more than 0.65 s to form the tail portion (7) of the container.
  14. 前述权利要求任一项所述的制备滴眼液制品的方法，其特征在于，所述能够使密封部分不可逆脱开的外力为不超过5～7岁儿童手指的平均捏合力，优选不超过17～27牛顿(N)。 The method for preparing an eye drop preparation according to any of the preceding claims is characterized in that the external force capable of irreversibly disengaging the sealing portion is no more than the average pinching force of the fingers of a 5-7 year old child, preferably no more than 17-27 Newtons (N).
PCT/CN2024/075261 2023-02-03 2024-02-01 Multi-chamber container for eye drops and manufacturing method therefor WO2024160253A1 (en)

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